tbuckley/cabot-search huggingface dataset:
Phenotypic and endotypic features of COPD associated with lung cancer development.
Authors: Kyeryoung Lee, David Cohn, Zongzhi Liu, Lei Ai, Hunki Paek, Lan Jin, Kalpana Raja, Minghao Li, Xingmin Zhang, Tomi Jun, Mitchell Higashi, William Oh, Ediz S. Calay, Radoslav Savic, Krish Ghosh, Andrew Kasarskis, Tommy Mullaney, Qi Pan, Eric Schadt, Xiaoyan Wang
Journal: Journal of Clinical Oncology (2022)

e13563 Background: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with multiple phenotypes and endotypes and associated with lung cancer development. In this study, we analyzed the clinical features of COPD including various phenotypic and endotypic features from the electronic health records (EHR) as the potential risk factors for lung cancer development in a large cohort of COPD patients. Methods: We identified a COPD cohort based on electronic Medical Records and Genomics (eMERGE) network COPD cohort identification algorithms with minor modifications from the Mount Sinai Data Warehouse (2000-2020) and followed the patients on the first diagnosis of lung cancer. The development of lung cancer in COPD patients was confirmed by manual chart review. We retrieved the clinical features from EHRs and conducted Kaplan Meier (KM) analysis and multivariable Cox-regression modeling for hazard ratio (HR) analysis. Results: We found that 3.8 % of COPD patients (824 out of 21,658) developed lung cancer. While COPD patients with emphysema and smoking history (former or current) showed an increased risk of lung cancer onset, patients with concurrent asthma and corticosteroid (ICS) inhalation history showed a reduced risk of lung cancer onset (adjusted HR in Table). Interestingly, COPD patients with higher eosinophil counts showed late onset of lung cancer (&gt;300 cells/ul, cancer rate at 5y=2.4%, p=&lt; 0.002; 150-300 cells/ul, cancer rate at 5y=2.9%, p=0.003) when compared to patients with low eosinophils count (&lt;150 cells/ul, cancer rate at 5y=3.4%) in a KM analysis. A multivariable analysis adjusted for age, gender, race, smoking status, COPD sub-phenotypes, severe exacerbation history, and ICS inhalation history showed a significantly lower risk of lung cancer in COPD patients with higher eosinophils count (150-300 cells/ul; HR: 0.82, 95% CI: 0.69-0.97, p=0.021 and &gt;300 cells/ul; HR:0.72, 95% CI: 0.57-0.89, p=0.003) when compared to those with low eosinophils count (&lt;150 cells/ul). Conclusions: Our study shows that many phenotypic and endotypic features of COPD are differentially associated with lung cancer development. High eosinophil levels, ICS usage, and concurrent asthma in COPD patients may reduce the risk of lung cancer development. [Table: see text]
Computed tomography based, 3D segmentation method for renal volume measurement in comparison to the actual renal volume of transplanted kidney: A prospective study
Authors: A. Galal, Y. Osman, M.H. Zahran, H. Refaie, M.E. Ghoneim, I. Saeed, M. Atteya, B. Ali-El-Dein
Journal: European Urology (2022)
Eleven years of experience with UTUC: Survival and renal function after kidney sparing surgery versus radical nephroureterectomy
Authors: N. Hendriks, J. Baard, H.P. Beerlage, B.M.A. Schout, R.C.M. Pelger, K.S.G. Doherty, G.M. Kamphuis
Journal: European Urology (2022)
EGFR gene aberrations in non-small cell lung cancer patients in the Crimea Republic.
Authors: Natalya N. Timoshkina, Natalia A. Petrusenko, Al-Nsour Rashed, Astanda K. Gvaramiya, Madina A. Gappoeva, Dmitriy A. Savchenko, Oleg I. Kit, Denis S. Kutilin
Journal: Journal of Clinical Oncology (2022)

e20514 Background: Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and remains the most commonly diagnosed human neoplasm with a poor prognosis. Significantly improving the clinical course of NSCLC, EGFR tyrosine kinase inhibitors are effective only against tumors carrying activating mutations in the EGFR gene, and their frequency varies depending on the patient population. The aim of the study was to analyze a retrospective group of Crimean patients with advanced NSCLC for the presence of EGFR gene aberrations and association with clinical outcome. Methods: We used DNA samples from FFPE blocks of tumor and non-tumor tissues of 72 European-type patients (aged 46-78 years, median 64 years, 82% - men, 18% - women) diagnosed with lung cancer (T1-1aN0-2M0-1, stage I-IV). The relative copy number of the EGFR gene was assessed by RT-qPCR using GAPDH and B2M as reference genes. Mutations (9 deletions in exon 19, L858R, T790M, L861Q, G719S/A/C, 3 insertions in exon 20, S768I) in the EGFR gene were determined using the Therascreen EGFR RGQ PCR Kit (Qiagen, Germany). Results: For Crimean population patients, the squamous subtype of NSCLC was more common (57%). EGFR copy number evaluation in patients with adenocarcinoma showed locus amplification in 9 patients (30%), no loss of copy number was recorded. In the squamous cell carcinoma group, locus amplification prevailed in 25 of 42 samples (59.6%) and a decrease in copy number was noted in 4 samples (9.5%). Differences in the frequency of aberrant changes in the relative copy number of EGFR in adenocarcinoma and squamous cell lung cancer groups were statistically significant (χ 2 = 11.04 at p = 0.003). The activating mutation frequency in adenocarcinoma samples was 9.7% (ex19del), which was lower than the frequency recorded in European adenocarcinoma patient populations (14.4%, p = 0.036). No EGFR mutations were found in cases of squamous cell lung cancer. The presence of mutations and/or changes in EGFR copy number were associated with shorter overall survival in patients who did not receive targeted and immune therapy (p = 0.034). Conclusions: The ex19del activating mutation of the EGFR gene frequency in adenocarcinoma samples was 9.7%. A more frequent EGFR alteration was detected when assessing the locus copy number in the tumor relative to the non-tumor tissue: changes were recorded for 30% of adenocarcinoma cases and 69.1% of squamous cell lung cancer.
Comparing overall survival of patients with metastatic uveal melanoma by sequence of Tebentafusp versus combination immune checkpoint inhibitors.
Authors: Sufana Shikdar, Silas Day, Alexandra Ikeguchi, Yuan Ying
Journal: Journal of Clinical Oncology (2022)

e21505 Background: Uveal melanoma is a rare melanoma subtype with poor outcome from immune checkpoint inhibition (ICI) compared to cutaneous melanoma. UM expresses high levels of Glycoprotein 100 (Gp-100) implicating potential sensitivity to tebentafusp (tebe), a novel immune-mobilizing monoclonal T cell receptor therapy. A recent phase 3 study compared tebe to investigator chosen standard of care (SOC) with crossover at progression. SOC regimens were single agent pembrolizumab, ipilimumab and Dacarbazine with 82% of SOC patients receiving pembrolizumab 1 . Other single arm studies suggest that survival with combination ICI is superior to single agent. We sought to compare overall survival (OS) of first or second line tebe in relation to combination ICI. Methods: Retrospective chart review at a single institution was conducted on patients with metastatic UM (mUM) treated with tebe on clinical trial between June 2018 and December 2021, either in first [NCT03070392] or second line [NCT02570308] setting. Patients were included if they received ipilimumab plus nivolumab either before or after tebe. Data including patient demographics and factors demonstrated in the phase 2 and 3 trials to correlate with survival including lactate dehydrogenase (LDH), size of largest liver lesion and early onset of rash with tebe were extracted. OS was the main outcome measure and was calculated as the time interval between the date of diagnosis of metastatic disease and date of death. Results: Six patients were identified in our data set as having received both ICI and Tebe, three in each sequence order. Mean characteristics were included in table. OS trended towards improvement in the cohort of patients who received tebe first in sequence both in OS in time from UM diagnosis (42.1 vs 63.5 months) (p = 0.21) and in OS in time from detection of mUM (29.8 vs 42.0 months) (p = 0.28), although neither difference was statistically significant given the small sample size. Conclusions: Our limited data demonstrate longer OS with tebe followed by combination ICI on progression compared to the reverse sequence. This comparison of patients at a single institution is underpowered to show a statistically significant OS difference but does demonstrate a trend in favor of first line tebe similar to the conclusive comparison of tebe and single agent ICI in the randomized trial. Reference: 1. Orloff, Marlana et al. Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in phase 3 randomized trial of first-line metastatic uveal melanoma. (2021): 9526-9526.[Table: see text]
MODL-03. Establishment of intraventricular Shh inhibition as a therapeutic option for young patients with medulloblastoma
Authors: Catena Kresbach, Melanie Schoof, Lea Holst, Tara Leven, Timur Yorgan, Antonina Wrzeszcz, Stefan Rutkowski, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract The prognosis of pediatric medulloblastoma is still dissatisfying today and tumor survivors often suffer from severe treatment-related morbidities. This poses an urgent need for more efficient therapies. Shh medulloblastoma is characterized by mutations in the Sonic Hedgehog (Shh) pathway, providing an elegant way of targeted therapy. The small molecule Vismodegib allosterically inhibits Smoothened (SMO), an upstream activator of Shh, and shows promising anti-tumor effects against Shh medulloblastoma. Unfortunately, Vismodegib caused severe bone deformities in preclinical studies and clinical trials, preventing its systemic application in children. In a mouse model, we established an intraventricular therapy with Vismodegib combining the benefits of targeted drug delivery and minimal systemic side effects. We compare intraventricular, oral, and placebo treatment regarding effects on survival, tumor biology, and bone morphology.Math1-cre::Ptch1Fl/Fl mice show a homozygous loss of Ptch1 in Math1-positive cells, resulting in Shh pathway overactivation and development of Shh medulloblastomas. At postnatal day 11-13, Math1-cre::Ptch1Fl/Fl mice were randomized in four treatment arms: Group A (n=14) received intraventricular placebo, B (n=12) received 200 mg/kd/d oral Vismodegib, C (n=16) received 0.2 mg/kg/d intraventricular Vismodegib, and D (n=9) received 1.6 mg/kg/d intraventricular Vismodegib. Kaplan-Meier survival curves show a significant survival benefit of 1.6 mg/kg/d intraventricular Vismodegib over placebo (p=0.003). While all intraventricular treated animals develop proliferative tumors at end of observation, investigations at an early time point after completed treatment show promising anti-tumor effects with reduced or absent proliferation in the cerebellum compared to placebo. Bone histology and X-ray analysis of intraventricular treated mice show intact femoral and tibial growth plates, in contrast to orally treated mice that develop severe skeletal malformations. Based on these preliminary experimental results, we conclude that intraventricular application of a SMO-inhibitor might evolve as a promising new way of targeted treatment of Shh medulloblastoma in children.
Characteristics of cytokine profiles of peripheral blood in patients with melanoma receiving checkpoint inhibitor therapy with disease progression.
Authors: Maria A. Teplyakova, Liubov Yu Vladimirova, Irina L. Popova, Aza A. Lyanova, Natalia A. Abramova, Anna E. Storozhakova, Ludmila A. Ryadinskaya, Natalia M. Tikhanovskaya, Irina A. Udalenkova, Elena A. Kalabanova, Sergey N. Kabanov, Aleksandr B. Sagakyants, Elena Yu Zlatnik, Oksana G. Shulgina, Ekaterina I. Zolotareva, Elena P. Ulianova, Viktoria V. Pozdnyakova, Yuriy V. Przhedetskiy
Journal: Journal of Clinical Oncology (2022)

e21509 Background: The limited range of patients clinically responding to checkpoint inhibitor therapy (CIT) is of interest and requires studying the immunological mechanisms underlying this phenomenon. It also remains to be decided or better clarified which biomarkers should be considered when selecting patients for immunotherapy. The purpose of this study was to evaluate some parameters of the cytokine profiles of peripheral blood in melanoma patients receiving CIT with the disease progression. Methods: The study included 11 patients aged 47-82 years with advanced melanoma. CIT (nivolumab 3 mg/kg once every 14 days or 240 mg once every 14 days) continued until the appearance of reliable signs of the disease progression (in combination with symptomatic deterioration of the patient's condition). The levels of cytokines (TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ) in the blood serum of patients were determined by ELISA before treatment, after 4 and after 8 injections. The results were expressed as specific content (units/mg). Results: All patients developed disease progression after immunotherapy. CIT was accompanied by different changes most pronounce after the 8 th CIT cycle. Levels of IL-1β, IFN-γ, IL-10 and α-TNF exceeded the values before CIT by 118%, 131%, 84% and 20%, respectively (5.2 [4.37; 6.1] versus 2.0 [0.44;4], p≤0.041, 3.9 [3.7;4.5] vs. 1.7 [0.5;3.5], p≤0.021, 6.5 [5.8 ;8.2] vs. 3.5 [3.2;5.4], p≤0.04; 4.1 [3.9;4.9] vs. 3.4 [3.2;3.9] pg/ml, p≤0.047). Levels of IL-6, on the contrary, decreased by the 8th CIT cycle by 32%: 5.1 [3.5; 6.1] versus 7.5 [6.2; 22.3] pg/ml, p≤ 0.045. Levels of IL-2 and IL-8 did not change. Conclusions: The revealed significant increase in levels of IL-1β, IFN-γ, IL-10 and α-TNF, as well as the IL-6 decrease, may indicate certain features of the cytokine profile of melanoma patients during the treatment, which may affect the imbalance of regulatory molecules and contribute to the disease progression.
Relationship between diabetes and its severity, frailty and adverse surgical outcomes among older adults with cancer.
Authors: Josue Martes, Amy L. Tin, Armin Shahrokni
Journal: Journal of Clinical Oncology (2022)

e24023 Background: Presence and severity of comorbid conditions impact surgical outcomes of older adults with cancer. The aim of our study is to evaluate the relationship between diabetes mellitus (DM), and preoperative HgbA1c (pHgbA1c) with frailty and adverse surgical outcomes among older adults with cancer. Methods: Retrospective study of patients aged 65 and older who underwent elective cancer surgery with at least one-day hospital stay in 2015-18 at our institution. For our primary aim, we assessed the association between DM and frailty, sociodemographic and clinical characteristics by reporting the characteristics stratified by presence of DM. Frailty was assessed using the Memorial Sloan Kettering Frailty Index (MSK-FI), which composes of 10 comorbidities and one functional component. This score ranges from 0-11, with higher score corresponding to greater frailty. Our secondary aim to assess the association between pHgbA1c and frailty was evaluated by a linear regression with pHgbA1c as the outcome and MSK-FI as the predictor. For our tertiary aim to assess the association between pHgbA1c and adverse surgical outcomes, we used a univariable logistic regression model with the outcome as the composite definition of 30-day readmission, 30-day emergency room visit, 30-day major complication, or 90-day mortality, and pHgbA1c as the predictor. We also used a multivariable logistics regression model, adjusting for age, gender, American Society of Anesthesiologist Performance Status (ASA-PS), and operation time.Analyses related to pHgbA1c excluded patients without pHgbA1c records. Results: Among 4417 patients, 1024 (23%) had DM and among those 403 (39%) had pHgbA1c values recorded. The results showed patients with DM were older, had higher ASA-PS, more comorbidities and higher MSK-FI scores than those without DM. Moreover, pHgbA1c was not found to be statistically associated with degree of frailty (β for one unit change in MSK-FI 0.11, 95% CI 0.00, 0.21; p = 0.057). Lastly, in both unadjusted and adjusted models pHgbA1c was not associated with adverse surgical outcomes (OR for both models, 0.99, 95% CI 0.83, 1.16, p = 0.9). Conclusions: In this cohort of patients whose pHgbA1c values were recorded, pHgbA1c was not associated with adverse surgical outcomes. Further studies are needed to confirm this study with more focus on perioperative care process of patients with DM and find cohorts whose pHgbA1c measurements can better predict frailty and adverse surgical outcomes.
Features of chromosome instability in Chinese early-onset colorectal cancers.
Authors: Xiangwu Zhou, Guijin Chen, Jinchun Zhuo, Xinyi Liu, Haixin Gao, Quanwang Yi, Mengli Huang
Journal: Journal of Clinical Oncology (2022)

e15519 Background: In recent years, the etiology and molecular mechanism of early-onset colorectal cancers (EOCRC) has evoking more and more attention. Previous studies suggested that EOCRC had unique somatic mutational characteristics, such as frequent mutations in genes of WNT signaling pathway. However, the features of chromosome instability in this particular subgroup of colorectal cancer remain unclear. Somatic copy number alteration (SCNA) is the main manifestation of chromosome instability. We performed a systematic analysis in regard to SCNAs in a large cohort of Chinese colorectal. Since the microsatellite instable (MSI-H) cancers rarely occurred SCNAs, only microsatellite stable (MSS) patients were included. Methods: A total of 1696 Chinese MSS CRC patients diagnosed in 2018-2020 were included. Early-onset were defined as patients diagnosed under 50 year-olds and the others were late-onset (LO). Genomic alterations and SCNAs were elucidated in all patients’ tumor specimen using next-generation sequencing (NGS) testing. Results: All patients were stratified as EOCRC (n = 439) and LOCRC (n = 1214). 3.87% EOCRC harbored germline cancer susceptibility genes (mainly APC and ATM) mutations while in the LOCRC counterpart the proportion was only 2.06% (mainly MUTYH and BRCA2). Of note, MYC amplification was detected in 71.43% EOCRC with copy-number gain and presented a trend to correlated with APC germline mutations (Fisher’s exact test, p-value = 0.07). In the other CRC (n = 1654) with no germline cancer susceptibility genes, genomic amplifications were detected in 831 (50.2%) cases. The frequency of 8q and 13q amplification were equal in EOCRC and LOCRC. However, EOCRC had higher proportion of 8p and 17q amplification, lower proportion of 20q amplification than LOCRC. Moreover, a higher ratio of EOCRC had high-level amplifications, mainly concentrated in 17q ( ERBB2, CDK12 and RARA) and 13q ( FLT3, CDK8 and FLT1), than LOCRC (23.7% vs 19.1%). Other high-level amplified genes include MYC, CCND2 and EGFR. EGFR high-level amplifications occurred more in EOCRC than LOCRC (13.5 % 2.6%), while CCND2 high-level amplifications were only detected in LOCRC. Gene copy number losses were detected in 195 (11.8%) cases. Loss of SMAD4, CDKN2A, CDKN2B, MAP2K4, PTEN and AMER1 genes were most recurrent. The incidence of SMAD4 (43.1% vs 22.9%), CDKN2B (11.8% vs 6.2%), MAP2K4 (7.8% vs 4.2%) gene losses were higher in EOCRC while the incidence of PTEN (13.9% vs 7.8%) and SMAD3 (6.9% vs 1.9%) gene losses were higher in LOCRC. Conclusions: EOCRC present different SCNA characteristics from LOCRC, including unique focal amplifications, distinct recurrent genes with copy number losses, and more high-level amplifications events mainly distributed in 17q and 13q. It can be reasonably speculated that MYC gene gain was a critical event correlated with familial mutations in EOCRC.
Booster third dose of SARS-CoV-2 vaccine effectively lifts the waning immune response of solid cancer patients.
Authors: Urska Janzic, Urska Bidovec-Stojkovic, Mohorcic Katja, Nina Fokter Dovnik, Marina Caks, Jerneja Debeljak, Peter Korosec, Matija Rijavec
Journal: Journal of Clinical Oncology (2022)

e18791 Background: Since cancer patients (pts) are at increased risk of severe morbidity and mortality due to COVID-19, SARS-CoV-2 vaccination is crucial to prevent severe disease course. The efficacy and longevity of vaccine protection, however, is still in question. Methods: In this prospective observational study we assessed immunogenicity of cancers patients on active treatment for solid cancers in two Slovenian Oncology Centres receiving SARS-CoV-2 vaccine by detection of anti-SARS-CoV-2 S1 IgG antibodies in serum; before, after first and second dose, 3 and 6 months (mo) after complete primary course of vaccination and 1 mo after the 3rd booster dose. Samples with ≥ 175 ng/ml were considered positive. Results: There were 125 pts included in the study, 112 completed the primary course of vaccination with 2 vaccine doses and 34 received the booster 3 rd dose. Out of 34 pts receiving booster 3 rd dose, the majority received mRNA based vaccines (88%) for the primary course of vaccination and all patients received mRNA based vaccines for the booster 3 rd dose. Median time from 2 nd to booster 3 rd dose of vaccine was 6.75 mo, median age of pts was 66 yrs and 59% were male. Patients were receiving chemotherapy (ChT), immune checkpoint inhibitors (IO) or targeted therapy (TT) in 9%, 56% and 35%, respectively. They achieved seroconversion in 94% after the 2 nd and in 97% after the 3 rd booster dose. Overall, the median anti-SARS-CoV-2 S1 IgG titer was 11,191 ng/ml (mean 25,394; range 0 – 100,000) after complete primary course of vaccination and 1892 ng/ml (mean 6413; range 0 – 72,000) 6 mo after, P &lt; 0.0001. However anti-SARS-CoV-2 S1 IgG antibodies increased significantly after the 3 rd booster dose with median antibody value 51,310 ng/ml (mean 51,787; range 0 – 100,000), P &lt; 0.001. Only one pt in this group got infected with SARS-CoV-2 and had a mild disease course. Conclusions: Cancer pts treated for solid malignancies achieve a high rate of seroconversion through the primary course of vaccination. However, significant waning of immunity against SARS-CoV-2 is observed 6 months thereafter, which can be potentiated with additional 3 rd booster dose of vaccine.
PATH-07. Diagnostic and therapeutic value of cerebrospinal fluid biopsy in pediatric brain tumors
Authors: Shaoqun Li, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The application of cerebrospinal fluid (CSF) biopsy in brain tumors is valuable. This paper further explores the diagnostic and therapeutic value of CSF biopsy in pediatric brain tumors. METHODS: In this study, children with primary brain tumor aged ≤18 years old in Guangdong Sanjiu Brain Hospital were enrolled．CSF next-generation sequencing (NGS) tests were required for all included patients. The genetic mutations in these children were analyzed. RESULTS: A total of 12 pediatric brain tumors who underwent CSF NGS were included in this study. 9 patients were brainstem glioma and 3 were pilocytic astrocytoma. The mutated genes were detected in 67% (8/12) patients by CSF NGS. In brainstem glioma, the rate was 67% (6/9), and the most common genes were H3F3A (5/6, 83%) and TP53 (5/6, 83%). Other detected genes included EGFR, CDK4 and NF2. H3F3A mutation is of great significance for the diagnosis and treatment of brainstem glioma, and CDK4 and EGFR are valuable for the treatment. In pilocytic astrocytoma, the deteaction rate was 67% (2/3), and the genes included KIAA1549-BRAF fusion, FGFR1 and PTPN11 mutations. KIAA1549-BRAF fusion is of great value in the diagnosis and treatment of pilocytic astrocytoma, and FGFR is valuable in the treatment. CONCLUSIONS: Fluid biopsy of CSF for pediatric brain tumors may be an important supplement to histological diagnosis, especially when histopathology is not available. The results are significant for the diagnosis and treatment of pediatric brain tumors.